title: Evaluation of a chimeric (uPA+/+)/SCID mouse model with a humanized liver for prediction of human metabolism.
abstract: A model that predicts human metabolism and disposition of drug candidates would be of value in early drug development. In this study, a chimeric (uPA+/+)/SCID mouse model was evaluated with three structurally distinct compounds (GW695634, a benzophenone, SB-406725, a tetrahydroisoquinoline and GW823093, a fluoropyrrolidine) for which human metabolism and disposition was characterized. Human metabolite profiles in plasma and/or urine were compared to those of chimeric (uPA+/+)/SCID and control CD-1 or (uPA+/+)/SCID) mice. GW695634 and SB-406725 exhibited primarily hepatic metabolism and were chosen as probes to assess which human metabolites would likely circulate systemically. GW823093 exhibited a combination of hepatic and extrahepatic metabolism such that renal excretion of drug-related material was ~2-fold greater in humans than in mice, and thus chosen as a probe to assess if the chimeric (uPA+/+)/SCID mouse would predict the urinary excretion of human metabolites. We observed that human metabolism and disposition was well represented for GW695634, somewhat represented for GW823093 and minimally represented for SB-406725. Collectively, the results of this and other studies suggest that while limitations for prediction of human metabolism and disposition exist, humanized chimeric mouse models can potentially represent informative new tools in drug discovery and development.
authors.affiliation: Preclinical Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Research Triangle Park, NC 27709, USA. mark.m.deserres@gsk.com
authors.forename: Mark
authors.initials: M
authors.lastname: De Serres
authors.forename: Gary
authors.initials: G
authors.lastname: Bowers
authors.forename: Gary
authors.initials: G
authors.lastname: Boyle
authors.forename: Claire
authors.initials: C
authors.lastname: Beaumont
authors.forename: Steve
authors.initials: S
authors.lastname: Castellino
authors.forename: James
authors.initials: J
authors.lastname: Sigafoos
authors.forename: Mehul
authors.initials: M
authors.lastname: Dave
authors.forename: Andrew
authors.initials: A
authors.lastname: Roberts
authors.forename: Vishal
authors.initials: V
authors.lastname: Shah
authors.forename: Katie
authors.initials: K
authors.lastname: Olson
authors.forename: Dipak
authors.initials: D
authors.lastname: Patel
authors.forename: David
authors.initials: D
authors.lastname: Wagner
authors.forename: Russell
authors.initials: R
authors.lastname: Yeager
authors.forename: Cosette
authors.initials: C
authors.lastname: Serabjit-Singh
mesh_terms: D000818:Animals; D001577:Benzophenones / Q000378:metabolism; D002678:Chimera / Q000378:metabolism*; D005260:Female; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000378:metabolism; D011759:Pyrrolidines / Q000378:metabolism; D013449:Sulfonamides / Q000378:metabolism; D044005:Tetrahydroisoquinolines / Q000378:metabolism
chemical_list: D001577:Benzophenones; C551634:N-(4-(((4-chloro-2-(3-chloro-5-cyanobenzoyl)phenoxy)acetyl)amino)-3-methylphenyl)sulfonylpropanamide; D004364:Pharmaceutical Preparations; D011759:Pyrrolidines; D013449:Sulfonamides; D044005:Tetrahydroisoquinolines; D010649:Phenylalanine; C551147:denagliptin